Abstract
CCL25/CCR9 is a chemokine/receptor pair controlling gut-specific leukocyte migration. We have previously demonstrated that CCL25/CCR9 interactions regulate murine colonic inflammation in acute colitis mediated by Dextran Sulfate Sodium (DSS) administration. We investigated here whether such interactions also play a role in chronic colitis. Chronic inflammation in wild-type (WT) and CCR9−/− mice was induced by one or several DSS cycles, each consisting of 7-day 2% DSS followed by a 10-day water oral administration. IBD scores were assessed by histological analysis. mRNA profiling of large intestinal tissues was performed by qPCR. Distribution and phenotypic characterization of dendritic cell (DC) subsets were assessed by flow cytometry. Our data indicate that one single DSS cycle can induce chronic inflammation in CCR9−/− mice. More profound chronic inflammation can be established in CCR9−/− mice after 2 DSS cycles as observed by IBD scoring and inflammatory cytokine mRNA levels. This is accompanied by an altered DC distribution with a progressive disappearance of colonic CD103+ DCs and an altered colonic plasmacytoid DC immunophenotype. Our results demonstrate that CCL25/CCR9 interactions regulate inflammatory immune responses in the large intestinal mucosa by balancing different DC subsets. These findings have important implications for the use of CCR9-inhibitors in therapy of human IBD as they indicate a potential risk for patients with large intestinal inflammation.
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